Poxviruses (of the family Poxviridae) are a family of the largest and most complex viruses that infect humans. They are large brick-shaped or ovoid complex dsDNA (double-stranded DNA) viruses capable of replicating in the cell cytoplasm independent of the cell nucleus and have in common the propensity to produce cutaneous lesions. Variola virus is the most virulent member of the Orthopox genus of viruses causing smallpox. It is specific for humans and has no other animal hosts. The primary reason for infection in humans is due to its ability to evade the host immune responses, and avoid complement activation. The prototype Orthopoxvirus, Vaccinia shows considerable sequence similarity to Variola and is the current smallpox vaccine. Other Orthopoxviruses such as cowpox and monkeypox viruses are maintained in one or a few host species but may cause localized or disseminated disease if transferred to other animals (Ref.1). Smallpox was declared eradicated in 1980 after the most successful vaccination campaign in history, using Vaccinia virus as the smallpox vaccine. The absence of a nonhuman reservoir for Variola virus made eradication possible. However, concerns about the possible use of the virus as a weapon of bioterrorism have increased in recent years. This is due to three reasons in addition to its lethality: 1) the virus is extremely contagious and thus self-perpetuates in the target population. 2) It is inexpensive to produce. 3) As it is the first and only human disease that has been eradicated, defensive measures (such as vaccination) and treatment protocols are unknown to the current generation of health care workers (Ref.2).

Variola usually enters through the respiratory tract. It attaches to the mouth, trachea or lung mucosa. The cells comprising of the mucous membrane are not tightly packed therefore allowing it to penetrate and move into the saliva. The existence of a unique viral attachment or cell surface receptor has not been established but more than one probably exists. A possible mode of entry is when it attaches to the host cell receptors which bind to the EGF (Epidermal Growth Factor). The virus enters cells via clathrin-coated pits or by direct fusion of the virus with the plasma membrane. Once the virus reaches the cell membrane, it enters the cell through endocytosis minus its membrane. Replication occurs within the cytoplasm of infected cells using virally-coded DNA-dependent RNA polymerase and other enzymes packaged within the infectious particle. Host biosynthetic processes are inhibited soon after poxvirus infection occurs. Viral DNA is synthesized as large concatemeric molecules that are resolved into unit length genomes. The progeny DNA serves as the template for the successive expression of intermediate and late genes. Poxvirus mRNAs are capped, methylated and polyadenylated just like standard eukaryotic mRNAs, but host cell mRNAs are modified in the nucleus and Vaccinia replicates in the cytoplasm. The early mRNA is translated into proteins that facilitate the uncoating and replication of the genome and allow transcription of a second class of intermediate genes. The intermediate mRNA is translated into factors that allow transcription of the late class of genes. The late mRNA is translated into the structural and enzyme components of the virion. The newly replicated progeny genomes are incorporated into the virions being assembled (Ref.3). Upon synthesis of the late structural proteins, characteristic viral membranes form in the cytoplasm and develop into infectious virus particles. The assembly of Vaccinia viruses is complex and produces two infectious forms of the virus. Most particles remain in the cell as IMV (Intracellular Mature Viruses), and are released when the cell bursts. However, some of the virus particles obtain a second wrapping of host cell membrane. This occurs at the trans Golgi and these double wrapped particles are called IEV (Intracellular Enveloped Viruses). Using actin, which polymerizes at their "lower" membrane surface, these IEVs push themselves through the cytoplasm and so arrive at the cell surface. Some IEVs push through the cells plasma membrane and remain attached to the cell surface. These are called CEVs (Cell-associated Enveloped Viruses). Others that push through the membrane are released and are called EEVs (Extracellular Enveloped Viruses). Some virus particles continue their outward journey on their actin tails by pushing the plasma membrane outward as microvilli. These projections become very long and make contact with other cells, thereby transferring infectious viral particles to them. The mode of entry into cells varies depending on the virus form. IMV particles enter by fusion with the plasma membrane whereas EEV particles are taken into the cell by endocytosis. The externalized forms of Vaccinia virus mediate cell-to-cell spread.

Poxviruses offer a large target for the immune system and they inhibit many host immune response proteins, including complement proteins, chemokines, serine proteases (serpins), IL-1Beta (Interleukin-1Beta), IL-18, Interferon, TNF-Alpha (Tumor Necrosis Factor) and TNF-Beta (Ref.4). Vaccination against smallpox is most effective by infection of the skin with Vaccinia virus, followed by extension of replication to the lymph nodes and spleen, which elicits cell-mediated and humoral immune responses that provide protection against infection with Variola virus. Consequently, all clinicians, including respiratory care clinicians, should be able to recognize the signs and symptoms of smallpox infection so that effective control measures, including isolation and care of infected individuals, can be implemented quickly in the event of a bioterrorism attack.